BBA - Reviews on Cancer (v.1855, #1)
Editorial Board (i).
Resistance to sunitinib in renal cell carcinoma: From molecular mechanisms to predictive markers and future perspectives by S.C. Joosten; L. Hamming; P.M. Soetekouw; M.J. Aarts; J. Veeck; M. van Engeland; V.C. Tjan-Heijnen (1-16).
The introduction of agents that inhibit tumor angiogenesis by targeting vascular endothelial growth factor (VEGF) signaling has made a significant impact on the survival of patients with metastasized renal cell carcinoma (RCC). Sunitinib, a tyrosine kinase inhibitor of the VEGF receptor, has become the mainstay of treatment for these patients. Although treatment with sunitinib substantially improved patient outcome, the initial success is overshadowed by the occurrence of resistance. The mechanisms of resistance are poorly understood. Insight into the molecular mechanisms of resistance will help to better understand the biology of RCC and can ultimately aid the development of more effective therapies for patients with this infaust disease. In this review we comprehensively discuss molecular mechanisms of resistance to sunitinib and the involved biological processes, summarize potential biomarkers that predict response and resistance to treatment with sunitinib, and elaborate on future perspectives in the treatment of metastasized RCC.
Keywords: Renal cell carcinoma; Kidney cancer; Targeted therapy; Sunitinib; Drug resistance; Biological tumor markers;
Corrigendum to “Liquid biopsies in lung cancer: The new ambrosia of researchers” [Biochem. Biophys. Act. 1846(2014) 539–546] by Christian Rolfo; Marta Castiglia; David Hong; Riccardo Alessandro; Inge Mertens; Geert Baggerman; Karen Zwaenepoel; Ignacio Gil-Bazo; Francesco Passiglia; Anna P. Carreca; Simona Taverna; Renza Vento; Daniele Santini; Marc Peeters; Antonio Russo; Patrick Pauwels (17).
Signal persistence and amplification in cancer development and possible, related opportunities for novel therapies by Shea A. Ford; George Blanck (18-23).
Research in cancer biology has been largely driven by experimental approaches whereby discreet inputs are used to assess discreet outputs, for example, gene-knockouts to assess cancer occurrence. However, cancer hallmarks are only rarely, if ever, exclusively dependent on discreet regulatory processes. Rather, cancer-related regulatory factors affect multiple cancer hallmarks. Thus, novel approaches and paradigms are needed for further advances. Signal pathway persistence and amplification, rather than signal pathway activation resulting from an on/off switch, represent emerging paradigms for cancer research, closely related to developmental regulatory paradigms. In this review, we address both mechanisms and effects of signal pathway persistence and amplification in cancer settings; and address the possibility that hyper-activation of pro-proliferative signal pathways in certain cancer settings could be exploited for therapy.
Keywords: Cancer hallmarks; Signal amplification; Hyper-activation of proliferative pathways; Cancer therapy; Apoptosis-effector genes; Sustained activation;
Regulation of cancer metastasis by cell-free miRNAs by Maša Alečković; Yibin Kang (24-42).
MicroRNAs (miRNAs) are integral molecules in the regulation of numerous physiological cellular processes that have emerged as critical players in cancer initiation and metastatic progression, both by promoting and suppressing metastasis. Recently, cell-free miRNAs shed from cancer cells into circulation have been reported in cancer patients, raising hope for development of novel biomarkers that can be routinely measured in easily accessible samples. In fact, establishing miRNA expression in the circulation likely has advantages over determination in primary tumor tissue, further augmenting the potential applications of miRNA detection in oncological practice. In addition, secretion of miRNAs impacting distant cell signaling or promoting the formation of a niche that sustains a distant tumor microenvironment allows for new treatment approaches to thwart cancer progression.
Keywords: Cell-free microRNA; Exosomes; Body fluids; Biomarker; Metastasis;
Epithelial–mesenchymal transition in pancreatic cancer: Is it a clinically significant factor? by Jia-Hao Jiang; Chen Liu; He Cheng; Yu Lu; Yi Qin; Yong-Feng Xu; Jin Xu; Jiang Long; Liang Liu; Quan-Xing Ni; Xian-Jun Yu (43-49).
Pancreatic cancer is one of the most aggressive solid malignancies. This aggressiveness is partly attributable to extensive local tumor invasion and early systemic dissemination as well as resistance to chemotherapy. Epithelial–mesenchymal transition (EMT) plays fundamental roles in embryonic development and in the differentiation of normal tissues and organs. EMT also plays critical roles in tumor formation, dissemination and drug resistance in pancreatic cancer. Emerging data suggest that inhibiting EMT may reverse the EMT phenotype and enhance the efficacy of chemotherapeutic agents against pancreatic cancer cells. Thus, an understanding of the molecular biology of EMT in pancreatic cancer may provide insights into the mechanisms of tumor invasion and metastatic progression and facilitate the development of alternative therapeutic approaches to improve the treatment outcomes for patients suffering from pancreatic cancer.
Keywords: Epithelial–mesenchymal transition; Pancreatic cancer; Tumorigenesis; Metastasis; Prognosis; Therapy;
Targeting the ubiquitin pathway for cancer treatment by Jia Liu; Shavali Shaik; Xiangpeng Dai; Qiong Wu; Xiuxia Zhou; Zhiwei Wang; Wenyi Wei (50-60).
Proteasome-mediated degradation is a common mechanism by which cells renew their intracellular proteins and maintain protein homeostasis. In this process, the E3 ubiquitin ligases are responsible for targeting specific substrates (proteins) for ubiquitin-mediated degradation. However, in cancer cells, the stability and the balance between oncoproteins and tumor suppressor proteins are disturbed in part due to deregulated proteasome-mediated degradation. This ultimately leads to either stabilization of oncoprotein(s) or increased degradation of tumor suppressor(s), contributing to tumorigenesis and cancer progression. Therefore, E3 ubiquitin ligases including the SCF types of ubiquitin ligases have recently evolved as promising therapeutic targets for the development of novel anti-cancer drugs. In this review, we highlighted the critical components along the ubiquitin pathway including E1, E2, various E3 enzymes and DUBs that could serve as potential drug targets and also described the available bioactive compounds that target the ubiquitin pathway to control various cancers.
Keywords: Cancer; SCF; Ubiquitin ligase; Deubiquitinating enzyme; Drug targets;
Pancreatic ductal adenocarcinoma: From genetics to biology to radiobiology to oncoimmunology and all the way back to the clinic by Emmanouil Fokas; Eric O'Neill; Alex Gordon-Weeks; Somnath Mukherjee; W. Gillies McKenna; Ruth J. Muschel (61-82).
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death. Despite improvements in the clinical management, the prognosis of PDAC remains dismal. In the present comprehensive review, we will examine the knowledge of PDAC genetics and the new insights into human genome sequencing and clonal evolution. Additionally, the biology and the role of the stroma in tumour progression and response to treatment will be presented. Furthermore, we will describe the evidence on tumour chemoresistance and radioresistance and will provide an overview on the recent advances in PDAC metabolism and circulating tumour cells. Next, we will explore the characteristics and merits of the different mouse models of PDAC. The inflammatory milieu and the immunosuppressive microenvironment mediate tumour initiation and treatment failure. Hence, we will also review the inflammatory and immune escaping mechanisms and the new immunotherapies tested in PDAC. A better understanding of the different mechanisms of tumour formation and progression will help us to identify the best targets for testing in future clinical studies of PDAC.
Keywords: Pancreatic cancer; Genetics; Biology; Chemotherapy; Radiobiology; Oncoimmunology;
Biological functions of hyaluronan and cytokine-inducible deubiquitinating enzymes by Suresh Ramakrishna; Bharathi Suresh; Kwang-Hyun Baek (83-91).
The modification of proteins through post-translation and degradation by the ubiquitin–proteasome system plays a pivotal role in a broad array of biological processes. Reversal of this process by deubiquitination is a central step in the maintenance and regulation of cellular homeostasis. It now appears that the regulation of ubiquitin pathways by deubiquitinating enzymes (DUBs) could be used as targets for anticancer therapy. Recent success in inducing apoptosis in cancerous cells by USP17, a cytokine-inducible DUB encoding two hyaluronan binding motifs (HABMs) showing direct interaction with hyaluronan (HA), could prove a promising step in the development of DUBs containing HABMs as agents in anticancer therapeutics. In this review, we summarize the importance of hyaluronan (HA) in cancer, the role played by DUBs in apoptosis, and a possible relationship between DUBs and HA in cancerous cells, suggesting new strategies for applying DUB enzymes as potential anticancer therapeutics.
Keywords: Apoptosis; Bioconjugates; CD44; DUB enzyme; Hyaluronan; Tumor;
Inhibitor of differentiation 4 (ID4): From development to cancer by Divya Patel; Derrick J. Morton; Jason Carey; Mathew C. Havrda; Jaideep Chaudhary (92-103).
Highly conserved Inhibitors of DNA-Binding (ID1–ID4) genes encode multi-functional proteins whose transcriptional activity is based on dominant negative inhibition of basic helix–loop–helix (bHLH) transcription factors. Initial animal models indicated a degree of compensatory overlap between ID genes such that deletion of multiple ID genes was required to generate easily recognizable phenotypes. More recently, new model systems have revealed alterations in mice harboring deletions in single ID genes suggesting complex gene and tissue specific functions for members of the ID gene family. Because ID genes are highly expressed during development and their function is associated with a primitive, proliferative cellular phenotype there has been significant interest in understanding their potential roles in neoplasia. Indeed, numerous studies indicate an oncogenic function for ID1, ID2 and ID3. In contrast, the inhibitor of differentiation 4 (ID4) presents a paradigm shift in context of well-established role of ID1, ID2 and ID3 in development and cancer. Apart from some degree of functional redundancy such as HLH dependent interactions with bHLH protein E2A, many of the functions of ID4 are distinct from ID1, ID2 and ID3: ID4 proteins a) regulate distinct developmental processes and tissue expression in the adult, b) promote stem cell survival, differentiation and/or timing of differentiation, c) epigenetic inactivation/loss of expression in several advanced stage cancers and d) increased expression in some cancers such as those arising in the breast and ovary. Thus, in spite of sharing the conserved HLH domain, ID4 defies the established model of ID protein function and expression. The underlying molecular mechanism responsible for the unique role of ID4 as compared to other ID proteins still remains largely un-explored. This review will focus on the current understanding of ID4 in context of development and cancer.
Keywords: ID4; bHLH; Cancer; Epigenetics; Development; Differentiation;
Portrait of the PI3K/AKT pathway in colorectal cancer by Stine Aske Danielsen; Peter Wold Eide; Arild Nesbakken; Tormod Guren; Edward Leithe; Ragnhild A. Lothe (104-121).
PI3K/AKT signaling leads to reduced apoptosis, stimulates cell growth and increases proliferation. Under normal conditions, PI3K/AKT activation is tightly controlled and dependent on both extracellular growth signals and the availability of amino acids and glucose. Genetic aberrations leading to PI3K/AKT hyper-activation are observed at considerable frequency in all major nodes in most tumors. In colorectal cancer the most commonly observed pathway changes are IGF2 overexpression, PIK3CA mutations and PTEN mutations and deletions. Combined, these alterations are found in about 40% of large bowel tumors. In addition, but not mutually exclusive to these, KRAS mutations are observed at a similar frequency. There are however additional, less frequent and more poorly understood events that may also push the PI3K/AKT pathway into overdrive and thus promote malignant growth. Here we discuss aberrations of components at the genetic, epigenetic, transcriptional, post-transcriptional, translational and post-translational level where perturbations may drive excessive PI3K/AKT signaling. Integrating multiple molecular levels will advance our understanding of this cancer critical circuit and more importantly, improve our ability to pharmacologically target the pathway in view of clonal development, tumor heterogeneity and drug resistance mechanisms. In this review, we revisit the PI3K/AKT pathway cancer susceptibility syndromes, summarize the known aberrations at the different regulatory levels and the prognostic and predictive values of these alterations in colorectal cancer.
Keywords: Colorectal cancer; PI3K/AKT pathway; Gene expression; Mutation; Copy number variation; MicroRNA;